Reference: JAMA. 2025 Aug 31 early online
Practice Point: While results of the ALONE AF trial might get some hype, don’t start discontinuing long-term anticoagulation for patients with ablated atrial fibrillation based on this analysis.
EBM Pearl: Composite outcomes are what researchers use when they’re worried no single outcome will be statistically significant given constraints of the trial. But combining completely dissimilar outcomes to achieve significance is unacceptable and a waste of resources.
In another episode of trials with egregious flaws being published in big-name journals, we have the ALONE AF trial, which claims that discontinuation of long-term anticoagulation is better than continuation for patients with atrial fibrillation (afib) at intermediate-to-high risk of thromboembolism after catheter ablation. Current guidelines recommend long-term oral anticoagulation for this population regardless of the perceived success of the ablation procedure to prevent ischemic stroke and thromboembolism.
Let’s just get to the meat of it so we can wax poetic about the massive problem with the composite. The ALONE AF trial randomized 840 adults in South Korea with afib s/p catheter ablation at intermediate-to-high risk of thromboembolism (CHA2DS2-VASc score of ≥ 1 for men or ≥ 2 for women) and who had no afib recurrence for at least a year to discontinue or continue long-term anticoagulation. The primary outcome was the first occurrence of a composite of—get this—stroke (ischemic and hemorrhagic), systemic embolism, and major bleeding event at 2 years. Honestly, we should really just stop here because that composite should be a deal-breaker. If something is not relevant or valid, it’s therefore not useful and not worth your time reading further. But to tame your curiosity, we’ll keep going anyway. Median CHA2DS2-VASc and HAS-BLED scores were both 2, 25% were women, 68% had paroxysmal afib, and discontinuation of anticoagulation occurred a median of 2.5 years after the ablation.
Results showed that at 2 years, the primary composite outcome occurred in 0.3% in the discontinuation group and 2.2% in the continuation group (absolute difference –1.9% [7 patients], 95% CI –3.5 to –0.3). When analyzed alone, major bleeding showed an absolute difference of −1.4% (95% CI −2.6 to −0.2) but none of the other single endpoints were significant, nor were a number of desperate add-on combinations of 2 at a time.
Now, the composite. At their best, composite outcomes are used in trials to increase event rates, which are sometimes needed to demonstrate a statistically significant effect of an intervention. A reasonable use of a composite is when every component reflects the same underlying risk and is an outcome that matters to patients. We’ve noted a few times over the years that when combining multiple outcomes and analyzing them as 1, there are 3 main red flags to look out for that signal a major threat to validity:
- Switching outcomes: when more or different (usually less clinically significant) outcomes are added to the composite during the trial to try to achieve significance
- Inflated composite outcomes: when the composite is significant but no single endpoint is significant
- A dominant surrogate endpoint: when no individual clinical outcome is significant but a single disease-oriented outcome (like microvascular disease of the eye without visual impairment) is significant and carries the composite over the line to significance
In this trial, combining ischemic stroke, systemic embolism, and vascular death would have made sense—they’re all major thromboembolic events with direct relevance to morbidity and mortality. But combining outcomes that essentially represent both the benefits and harms of the 2 interventions being compared is something we’ve never really talked about, because we didn’t think we had to. But here we are. In the ALONE-AF trial, we can clearly see that we have a wildly inappropriate combination of outcomes being analyzed as a composite (stroke, systemic embolism, and major bleeding event), but we also have a protocol change. Per the supplement, the investigators added 6 additional secondary endpoints that thankfully were not added to the primary composite, but they were used to create several new secondary composites, none of which were significant. All to say, these data are riddled with threats to validity, and we really can’t do much with this information other than to wish the investigators had left the data the af alone.
Maybe stopping long-term anticoagulation is the right thing to do for these patients. Maybe it isn’t. But we all deserve more than maybes, and so do our patients.
For more information, see the topic Ablation Therapy for Atrial Fibrillation in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, MPH, FACP, Senior Deputy Editor at DynaMed; Claire Symanski, PhD, Medical Editor and Team Lead for ENT at DynaMed; McKenzie Ferguson, PharmD, BCPS, Senior Clinical Writer at DynaMed; Rich Lamkin, MPH, MPAS, PA-C, Clinical Writer at DynaMed; Matthew Lavoie, BA, Senior Medical Copyeditor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor II at DynaMed; and Jennifer Wallace, BA, Senior Associate Editor at DynaMed.